Trabectedin (Ecteinascidin-743, ET-743) is a tetrahydroisoquinoline alkaloid initially isolated from a marine organism Ecteinascidia turbinata, and now mainly is prepared by chemical synthesis. Trabectedin has a unique and complex mechanism of action. It can inhibit the transcription of heat shock inducing genes, and can also interact with the transcription-coupled nucleoside excision repair system, resulting in the formation of lethal DNA strand. Trabectedin has a strong in vitro activity against multiple tumor cell lines, such as soft tissue sarcoma, leukemia, melanoma, breast cancer, non-small cell lung cancer, and ovarian cancer.
The structure of ET-743 (Formula I) is as follows:

ET-743 is a complex compound with a limited solubility in pure water. The solubility of ET-743 in water can be increased by adjusting the pH of the solution to 4. However, ET-743 has a poor thermal stability. It rapidly degrades at room temperature (25° C.), and can only be stored for 1 month when refrigerated at 5° C. Therefore, trabectedin can only be long-term stored at −20° C., which greatly limits the clinical application thereof. Thus, it is necessary to improve the thermal stability of ET-743 by means of pharmaceutics. Meanwhile, it is also a great challenge for those skilled in the art.
The main impurities in trabectedin are ET-701, ET-745, ET-759B and ET-789A (Synthesis of Natural Ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from Cyanosafracin B, Journal of Organic Chemistry, 2003, 68(23), Page 8859-8866). Among them, the impurity ET-701 is a hydrolysate, and is the main impurity during the processes of lyophilization and storage of the formulation; and the impurity ET-745 is a reduction product of trabectedin. Their structures are as follows:

WO 0069441 discloses a sterile lyophilized formulation, comprising ET-743, mannitol and a phosphate buffer. The lyophilized formulation can be used for intravenous injection after being reconstituted and diluted. However, the formulation is not stable for long-term storage under refrigeration or at room temperature. It has to be stored at −15 to −25° C. in the dark. CN102018714A discloses a ET-743 lyophilized formulation, comprising a disaccharide selected from the group consisting of lactose, sucrose, and trehalose. In the study, it was found that these formulations showed the degradation of the active ingredient when stored for 3 months under accelerated conditions of 40°C./70% RH, suggesting that these formulations are still not stable if being stored for a long time. Therefore, it is very necessary to develop a novel and stable ET-743 formulation.